Porphyrins, the so-called “expanded porphyrins,” and related polypyrrole structures are members of a class of macrocycles capable of forming stable complexes with metals. The metal is constrained (as its cation) within a central binding cavity of the macrocycle (the “core”). The anions associated with the metal cation are found above and below the core; and are called apical ligands. Examples of this class of macrocycles are porphyrins, porphyrin isomers, porphyrin-like macrocycles, benzoporphyrins, texaphyrins, alaskaphyrins, sapphyrins, rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.
One preferred class of macrocycles is the texaphyrins. Texaphyrins are aromatic pentadentate macrocyclic compounds that have the ability to integrate metals within their core to form complexes known as “metallotexaphyrins”. Texaphyrins and metallotexaphyrins have been described as being useful as MRI contrast agents, fluorescent imaging agents for cancer, plaque, and retinal diseases, as radiosensitizers and as chemosensitizers in both oncology and atherosclerosis, and as photosensitizers in photodynamic therapy in oncology, atherosclerosis, and ophthamology. They have also been described as having the ability to hydrolytically cleave phosphate esters such as RNA, and to photolytically cleave RNA and DNA. Texaphyrins are aromatic benzannulene compounds containing both 18π- and 22π-electron delocalization pathways. Texaphyrin molecules absorb light strongly in the tissue-transparent 700-900 nm range, and they exhibit selective uptake (or biolocalization) in certain tissues, particularly regions such as liver, atheroma or tumor tissue, and neovascularized regions. Such selectivity can be detected by magnetic resonance imaging (for example with paramagnetic metal complexes) and by fluorescence.
Accordingly, advantage may be taken of this property to provide a means for selectively treating tumors, plaque caused by atherosclerosis, retinal diseases, and the like, as disclosed in the publications incorporated by reference below in the detailed description of the invention. Notwithstanding these properties, it has remained desired to provide new MTDs having a range of physicochemical properties, such as improved solubility and/or lipophilicity, lower toxicity, and improved stability, but still retaining the basic attribute of selective localization.
One method of accomplishing these goals would be to change the properties of existing metallotexaphyrins by modifying the functional groups covalently attached to the macrocycle, and/or by changing the core metal. However, preparations of such MTDs require complicated syntheses, since each compound is necessarily made by a different synthetic route, and/or is derived from different starting materials. Accordingly, there remains a need for a convenient method for preparing a library of texaphyrin derivatives, which vary in their physicochemical properties, and can be synthesized easily and efficiently in high yield. The present invention provides such a method by modifying the apical ligands associated with the metal component of existing metallotexaphyrins to provide a library of MTDs having a wide range of physicochemical properties.